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LYFE SCIENCES
Project: HERA
NM_001127208.2:c.2926C>T
p.Gln976Ter  ·  TET2
ACMG/AMP
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Classification rationale
1

The TET2 c.2926C>T (p.Gln976Ter; p.Q976*) variant has been reported in curated somatic cancer resources and has not been reported in ClinVar.

oncokb ↗ clinvar ↗
2

This variant is present at very low frequency in population databases, with allele frequency 7.96388e-06 in gnomAD v2.1 and 2.47815e-06 in gnomAD v4.1, both below the PM2 threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Available gene-level studies support TET2 loss-of-function biology and structural importance of the C-terminal catalytic region, but no variant-specific functional assay for p.(Gln976Ter) was identified.

PMID:21057493 ↗ PMID:24315485 ↗ oncokb ↗
4

Computational review showed no significant predicted splice effect by SpliceAI, with a maximum delta score of 0.01; REVEL was unavailable, and BayesDel score 0.294732 did not provide sufficient support for PP3 or BP4 for this nonsense variant.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 7.96388e-06; MAF= 0.00080%, 2/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.62022e-05; MAF= 0.00462%, 1/21644 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.47815e-06; MAF= 0.00025%, 4/1614108 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56172e-05; MAF= 0.00156%, 1/64032 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.294732.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105020525, n = 16 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ976
Hotspots ↗